BMP-7 Protein Complex
Hannah Regan '12
In embryonic development, one of the most
basic and important processes is axis patterning, that is, which side
of the organism will be its front, its two sides, its top and bottom.
Within the organism, axis patterning determines the structure of
tissues as well as their placement. This patterning is often achieved
through protein gradients (such as the
bicoid gradient4 in Drosophila
signaling ligands. On one end of the
axis there will be a high protein concentration that fades until it is
essentially non-existent at the other end of the axis. The
concentration of the protein sends signals of varying strength to cells
that cause them to follow a certain developmental pathway.
This gradient is often achieved through
the signal protein by another ligand: the signal protein decreases in
expression along the axis because it is repressed by a high
concentration of a protein that binds the signal and inhibits its
Bone Morphogenetic Proteins (BMPs) are
extracellular signaling proteins that play crucial roles in both
embryonic development and adult tissue regeneration processes. One of
the evolutionarily oldest signaling pathways, BMPs are required for
patterning of the embryonic axes. When a BPM ligand binds to a surface
receptor protein on a cell, it initiates a signal cascade (such as the
), with the end result of switching on or off certain
in the nuclear DNA. BMPs are regulated by various classes of
antagonists that can block its binding interface and prevent it from
contacting the cell surface receptors.
believed to have evolved from the same ancestral
protein as BMP72
. It was implicated as an important developmental protein when its
ability to rescue Xenopus embryos that had been ventralized was
discovered1. It is an extracellular cystine-
knot protein that exclusively binds BMP and thus inhibits its function6.
Noggin is required for proper neural tissue development in embryos and
proper differentiation of the embryonic axes.
II. BMP-7 Structure
a homodimer with two wing shaped monomers, each of which is anchored in
a cystine-knot core. Each 'wing' is formed
by two pairs of antiparallel ß-strands that are referred to
as finger 1
and finger 2.
There is one α-helix
per monomer that extends for 3.5 turns
of each monomer
in two main ways: through contacts between the fingers, and by the
cystine-knot conformation. Finger 1 contains a 13 residue
Ω-loop with five polar
residues that are in contact with the solvent
and six non-polar
residues that contribute, along with eight residues
(also non-polar) from finger 2, to the stability of the interface
between the fingers
Each wing is
anchored in a
'core' region that
contains a ten-membered cystine
is composed of eight residues linked by two disulfide bonds
A third disulfide bond passes through the eight membered ring to
form the ten membered knot
The BMP-7 dimer is formed by the interactions
between the α-helix
of each monomer and the concave shape formed by the finger region
of the opposite monomer and by an interchain disulfide bond
residues 103 on each chain
Upon binding by Noggin, BMP-7 undergoes a
each wing goes from relatively flat
to a curled conformation
Similar to BMP-7,
Noggin is a dimer, the C-terminal domain of
each monomer has two regions of β-sheets that are refered to
as finger 1
and finger 2.
The N-terminal region of the monomer is about 20
residues long, and is referred to as the clip domain,
a helical domain
extends from finger 1 up to the part of the monomer
that participates in dimerization
The cystine knot in Noggin
also serves to
stabilize the conformation
of the protein and maintain its integrity. In Noggin, unlike BMP, the
cystine knot is made up of a ten-membered
ring that has two disulfide
A third disulfide bond between two cystine residues not in the ring
structure passes through it to complete the knot
that are not in the ring structure.
The noggin dimer is formed by
contact between α-helix
4 of each monomer and by the disulphide bond between
residue 232 of each monomer
Noggin has a heparan
binding domain between α-helix 3 and
This domain binds to
proteoglycans 5on cell surfaces,
which may play a key role in
determining the Noggin gradient in the extracellular matrix2.
Noggin BMP-7 Antagonism
has a hydrophobic 'pocket' of
5 residues where it binds to receptors
The clip of the Noggin
antagonist has a proline
residue, the hydrophobic ring of which fits into this
and anchors Noggin to BMP-7 as well as prevents BMP-7 from binding its
BMP-7 has another receptor
defined by 5 residues
Blocked by the C-terminal end of the clip domain and by the tips of
fingers 1 and 2
are three disease causing
mutations that are identified in Noggin
that result in apical joint fusion.
Proximal symphalangism is the result of six residue point mutations:
Pro35Arg, Cys184Tyr, Gly189Cys, Ile220Asn, Tyr222Cys/Asn, Pro233Leu
These mutations likely interfere with Noggin's
ability to form a dimer.
Tarsal/carpal coalition syndrome is the result of
three point mutations: Arg204Leu, Pro35Arg, Tyr222Cys
These mutations prevent Noggin from binding
effectively to BMP-7.
Multiple syntosis syndrome is the result of one point mutation:
function, Noggin cannot bind BMP-7
to inhibit its function and establish a protein gradient. This
results in mutations in bone development in embryos.
De Robertis, E.M., Kuronda, H. 2004. Dorsal-
Ventral Patterning and Neural Induction in Xenopus
Annu. Rev. Cel Dev. Biol. 20: 258-308.
Wiater, E., Rodriguez-Leon, J., Economides, A.N., Kwiatkowski, W.,
Affolter, M., Vale, W.W., Izpisua Belmonte, J.C., Choe, S. 2002.
Structural basis of BMP signalling inhibition by the cystine knot
protein Noggin. Nature 420: 636-648.
 Griffith, D.L., Keck,
P.C., Sampath, T.K., Rueger, D.C., Carlson, W.D.
1996. Three-dimensional structure of recombinant human osteogenic
protein 1: Structural paradigm for the transforming growth factor
Β Superfamily. Proc. Natl. Acad. Sci. USA
H.D. 2009. The diffusion-based model for
of the Bicoid protein gradient. Diagram. Nature Reviews
S., Viviano, B.L., Economides, A.N., Saunders, S. 2002. Heparan sulfate
proteoglycans retain Noggin at the cell surface: a potential mechanism
for shaping bone morphogenetic protein gradients. Journal of
Biological Chemistry 277: 2089-2096.
 Walsh, D.W., Godson,
Brazil, D.P., Martin, F. 2010. Extracellular BMP-antagonist regulation
in development and disease: tied up in
knots. Trends in Cell Biology 20: 2440256.
Silva, Nathan and David Marcey. Intro to Jmol Scripting.
Acknowledgements to Karen Hicks' Developmental Biology class
for background information on developemental processess outlined in